Principles of nuclear metabolic imaging. Prof. Dr. Alex Maes AZ Groeninge Kortrijk and KULeuven Belgium

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1 Principles of nuclear metabolic imaging Prof. Dr. Alex Maes AZ Groeninge Kortrijk and KULeuven Belgium

2 I. Molecular imaging probes A. Introduction - Chemical disturbances will precede anatomical abnormalities in disease. For example, genetic mutations will precede clinical symptoms of cancer by many years. - Diagnostic procedures using imaging probes which detect biochemical abnormalities will permit earlier detection of disease.

3 - Imaging probes and drugs share common concepts in structural design and principle of action because they target the same enzymes, receptors and neurotransmitter systems. - Drugs block or inhibit their targets and thus restore chemical imbalances resulting in control or remove clinical symptoms. -Molecular imaging probes probe the same targets assessing their functional status. -Thus, drugs and molecular imaging probes will be structural analogs of each other.

4 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

5 B. Molecular probe design: general principles - Investigation of living organisms must be performed with a minimum of interference with the system under investigation. - The introduction of radioactive molecules produces only minimal disturbances due to the extremely low mass of the probe.

6 Criteria for selecting and using molecular imaging probes 1. Target specificity 2. High membrane permeability to reach target areas 3. Use of molecules specific to one biochemical pathway 4. High affinity of the molecular probe for its tissue target 5. Rapid blood pool clearance 6. No or slow peripheral metabolism of the probe 7. High specific activity to trace the process without exerting mass effects on the target molecule. 8. Low non specific binding

7 Probes used in positron emission tomography: Positron emittors

8 Cyclotron CYCLOTRON & RADIOCHEMISTRY ( + emissie) 11 C, 18 F, 13 N, 15 O 511 kev 511 kev o Annihilation Radiation

9 Detection in Positron emission tomography (PET): Localization of positron annihilation

10 The Multidisciplinary Art of PET PET SCANNER coincidence detection IMAGE 3D-biodistribution (whole-body)

11 C. Types of molecular imaging probes 1. Probes for determination of perfusion These probes have no specific structural requirements, except for high vascular membrane permeability without specific macromolecular targets in tissue.

12 2. Probes based on stoichiometric binding interactions These imaging probes are radiolabeled drug derivatives or analogs binding with a high degree of specificity to receptor systems, neurotransmitter presynaptic reuptake carriers or enzymes. The probes do not experience chemical modifications as a result of the interaction. Trapping of receptor mediated probes is the result of stoichiometric binding to the target site.

13 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

14 MSA vs IPD postsynaptic PET measures N = 9, Raclopride discrimination : 9/9 Raclo best correlation to motor impairment Antonini et al, Brain 1997

15 3. Probes based on enzyme-mediated transformations - These probes are characterized by trapping in tissue the product of a specific interaction of the probe with an enzyme. - The interaction will produce a chemical transformation of the original probe catalysed by the enzyme. - The product of the enzyme-mediated transformation is impermeable to cell membranes and is retained in tissue in proportion to the rate of reaction of the enzyme-mediated process. This is called metabolic trapping.

16 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

17 Examples of PET imaging probes acting through this mechanism: - Hexokinase mediated trapping of FDG-6-phosphate after fluorodeoxyglucose (FDG) administration.

18 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

19 Most used PET tracer for clinical oncology Fluor-18 deoxyglucose = FDG Half-life-time: 110 minutes, iv injection

20 Production of fluor-18 deoxyglucose Cyclotron

21 METABOLISM TRACERS Glucose 18 F-FDG CH 2 OH O HO OH OH 18 F fluorine18-fluorodeoxyglucose

22 What is PET able to do with FDG? - Imaging and measurement of glucose uptake - Into normal tissue - Brain, heart, liver and other organs - In cancer tissue - Brochial, skin, colon, liver, lymph node, esophagus, larynxcancer - in inflammation

23 Normal Cell Neoplastic Cell Glucose 6-phosphatase FDG-6-P 18 FDG Glucose 6-phosphatase FDG-6-P Glycolytic pathway Hexokinase Hexokinase Glycolytic pathway G6P Glucose 6-phosphatase D- glucose G6P Glucose 6-phosphatase (inflammatory cells)

24 Whole body FDG PET lymphoma

25 FDG avidity Variability within same histological subtype: example DLBCL

26 Vocal cords speaking silence axial axial coronal coronal

27 Breast feading axial Mip

28 brown fat axial coronal mip

29 Infections toxoplasma NHL

30 Examples of PET imaging probes acting through this mechanism: - Fluorodeoxythymidine (FLT) used in the assessment of DNA replication based on the thymidine kinase-mediated phosphorylation to its 5 phosphate. - - At the time of PET imaging (<2 h), this monophosphate is metabolically trapped in tissue. With longer exposure times, the monophosphate would be phosphorylated by cellular kinases to the di- and tri-phosphate, and the latter incorporated into DNA.

31 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

32 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

33 II. Instrumentation for molecular imaging

34 Structural Imaging Radiology planare X-Ray CT echography Magnetic Resonance Imaging Metabolic Imaging Nuclear Medicine planar scintigraphy SPECT PET MRI

35 PET SPECT CT

36 Metabolic Imaging Clinical symptoms Structure Sensitivity & Specificity Function Metabolism Molecular abnormalities Structural Imaging Ultrasound / CT / MRI Metabolic Imaging PET / SPECT / (MRS)

37 Sensitivity of imaging modalities RX / CT MRI US PET SPECT Structural sensitivity millimeter centimeter 10-1

38 Sensitivity of imaging modalities RX / CT MRI US SPECT PET Biological Sensitivity millimolar nanomolar picomolar 10-6

39 modalities available for molecular imaging in humans Nuclear medicine SPECT-CT PET-CT SPECT PET Radiology CT MRI/MRS/fMRI

40 Whole-body 18-FDG PET - 18 F KeV o KeV > 60 min 45 min Injection of 6.5 MBq/kg FDG start scan from pelvis up to head and down to toes

41 PET Advantages: many tracers available isotopes: 15 O, 13 N, 11 C, 18 F very good sensitivity quantification possible Disadvantages: cyclotron needed limited spatial resolution positron range 11 C - Methionine 18 F - FDG

42 What is CT able to give us? - Visualisation of normal tissue - Vessels, intestine, bone, muscle - Changes in morphology - anatomic variants - organ-enlargement - pathological changes - BUT: - Is not able to distinguish distinctly between malignant and benign changes

43 CT Advantages: Anatomical imaging High spatial resolution Fast Disadvantages: Limited use for visualising soft tissue (eg WM vs GM) Radiation exposure can be high Contrast agents

44 PET/CT Combination of function PET positron emission tomography and morphology CT computed tomography

45 What is PET/CT?

46 PET/CT: PET and CT in a single machine - Combination: - Functional information from PET - morphological information from CT - Time saving: - Reduced data acquisition time of PET/CT compared to PET alone - 45 minutes vs minutes

47 PET-CT FDG-PET Advantages: Single examination Easy registration CT for attenuation correction Combined reading Disadvantages: High cost Extra radiation Contrast agents Breathing artifacts possible

48 Modalities available for molecular imaging in small animals Pinhole SPECT Small animal PET Optical imaging Micro CT Micro MRI/MRS

49 FDG-PET in Oncology Diagnosis Staging Prognosis Therapy Monitoring Metabolic characterization of structural lesions Whole-body screening Correlation with response rate and survival Responders versus Non-responders

50

51

52 Metastases at distance

53 What is happening 3 months later

54 FDG uptake as prognostic marker in lung Ca Vansteenkiste et al, JCO ptn

55 Level of FDG uptake predicts risk for recurrence in melanoma patients presenting with lymph node metastases Bastiaannet et al, Ann Surg Oncol 2006 Jul;13(7):

56 Therapy evaluation PreCRT A PostCRT C A B C D B D Tumor-to-liver uptake ratio: 37 Tumor-to-liver uptake ratio: 6 Primary Tumor: deltatur: 83%

57 Radiotherapy volume change CT planning PET/CT planning

58 Biochemical recurrence of prostate cancer Schmid DT, Hany TF. (2005) Radiology. May;235(2): PSA 2.1 ng/ml 10 d after surgery: 0.12 ng/ml Actually after 1 year: 0.00ng/ml

59 FDG PET 18 F-FDG PET h00383 Follow up of low grade (II) glioma since 4 years, clinical suspicion of relapse; MRI: left frontotemporal lesion with focal zone of contrast captation

60 Methionine PET 11 C-MET PET h00383 Histology : Glioma grade II

61 FDG PET 18 F-FDG PET h00072 Glioma grade II status post resection and 60 Gy, clinical deterioration, MRI: frontotemporal tumor recurrence

62 Methionine PET 11C-MET PET h Histology: glioma grade III

63 Alzheimer FDG PET

64 Michael E. Phelps - PET Molecular Imaging and Its Biological Applications - Springer

65 Imaging of amyloid plaques A4 immunohistochemic staining [18F]DV73 autorx

66 PET/CT 13 NH Perfusion Rest Stress

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